Genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one) Is Effective in Reducing Symptoms of Huntington's Disease in Females of the R6/1 Mouse Model.

BACKGROUND

Huntington's disease (HD) is an inherited (autosomal dominant) disorder caused by the occurrence of a pathogenic variant of the HTT gene. The genetic defect consists of an expansion of CAG repeats in exon 1, resulting in the production of a toxic misfolded huntingtin protein that forms aggregates. Currently, there is no registered therapy for this severe, neurodegenerative disease. Recent studies have demonstrated that treatment with genistein (4',5,7-trihydroxyisoflavone or 5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one), which acts by stimulating autophagy through a FOXO3-dependent process, can ameliorate behavioral abnormalities and improve biochemical parameters in the R6/1 mouse model of HD. However, although HD occurs in humans with similar frequency in men and women, the effects of high dose (150 mg/kg/day) of genistein on HD mice were tested previously only in males, because of concerns regarding potential ambiguity in interpretation of the results caused by structural similarities between genistein and estrogens. Nevertheless, as potential anti-HD therapies should be evaluated in both sexes, in this work the effects of genistein administration on behavior, levels of selected hormones, and biochemical parameters were evaluated in R6/1 female mice.

METHODS

Several behavioral tests, including the Rota-rod test, elevated-plus maze, open field test, and Morris water maze, were performed using R6/1 (HD) and control female mice treated with or without genistein at 150 mg/kg/day. We determined the levels of selected hormones and biochemical parameters in these animal groups. Genistein treatment was initiated at 16 weeks of age, shortly after the onset of symptoms at 14 weeks of age, and tests were conducted at 16, 22, and 30 weeks of age.

RESULTS

Genistein was effective in improving behavioral outcomes (p < 0.05 for all tests vs untreated animals) and improving hormonal and biochemical parameters (p < 0.05 for all tests) in female R6/1 (HD), similarly to results reported previously for males of the same line.

CONCLUSION

Genistein effectively reduced symptoms of HD in both male and female R6/1 mice.